Compositions comprising at least one polyol and at least one anesthetic

ABSTRACT

An injectable sterilized aqueous composition including at least one hyaluronic acid, at least one polyol and at least one local anesthetic chosen from the group made of benzocaine, chloroprocaine, procaine, etidocaine, aptocaine, chlorobutanol, diamocaine, dyclonine, guafecainol, polidocanol, mepivacaine, prilocaine, articaine, bupivacaine, ropivacaine, tetracaine and salts thereof and isolated isomers thereof. The invention also relates to a process for adapting the rheological properties of a heat sterilized injectable aqueous composition. The invention also relates to a process for producing an injectable sterilized aqueous composition according to the invention, and also to uses of said injectable sterilized aqueous composition according to the invention.

This is a Continuation of application Ser. No. 14/708,776 flied May 11,2015. The entire disclosures of the prior applications are herebyincorporated by reference herein their entirety.

The invention relates to the field of biodegradable gels and hydrogelsused as biomaterials and more particularly in the medical and aestheticsfields.

Hyaluronic acid has been used for more than fifteen years in theaesthetics field, where it has proved to be harmless and effective. Atpresent, in the market of esthetic filling gels or fillers, gels basedon crosslinked hyaluronic acid originating from biofermentation are themost widely used.

Among the medical applications, mention will for example be made ofinjections for replacing biological fluids that are deficient forexample in joints in order to replace synovial fluid, injectionfollowing a surgery in order to prevent peritoneal adhesions,periurethral injections for treating incontinence and injectionsfollowing surgery for long-sightedness.

Among the aesthetics applications, mention will for example be made ofinjections for filling wrinkles, fine lines or skin defects orincreasing volumes, for example the lips, the cheekbones, etc.

Use of hyaluronic acid originating from biofermentation in fields suchas the filling of wrinkles, viscosupplementation, ophthalmic treatmentor else the treatment of urinary incontinence is acknowledged andappreciated all the more since, owing to its natural presence in thehuman body, and more particularly in the dermis, synovial fluid andvitreous body, the risks due to side effects are minimized.

Numerous patent applications or publications have been filed orpublished on hyaluronic acid-based compositions comprising, in additionto the hyaluronic acid, active agents or excipients for modifying orimproving the properties of the composition according to the particularapplications.

For example, application WO 2013/186493 discloses hyaluronic acidcompositions including a sucrose octasulfate and application WO2014/032804 discloses hyaluronic acid compositions including a vitamin Cderivative.

Likewise, hyaluronic acid-based compositions comprising a polyol aredescribed in the prior art.

In application WO 2007/077399 In the name of Anteis, compositions fordermatological use based on hyaluronic acid or a salt thereof and on apolyol are presented. The addition of polyol has the effect of limitingthe degradation of the rheological properties of the compositions duringsterilization with moist heat.

Application WO 2008/068297 In the name of Pierre Fabre Dermo Cosmetiquedescribes protective effects, in particular in vivo, of the addition ofmannitol to hyaluronic acid compositions.

Application WO 2007/128923, in the name of Anteis describes thepreparation of a biocompatible gel comprising glycerol.

Application WO 2010/136694 In the name of Anteis discloses an injectablecomposition based on crosslinked hyaluronic acid, containing glycerol,the composition being sterilized by moist heat.

Finally, the publication “Hyaluronic acid combined with mannitol toimprove protection against free-radical endothelial damage: ExperimentalModel” (Belda-Journal of cataract and refractive surgery (2005)-31,1213-1218 provides details of the effects, in particular the in vivoeffects, of the addition of mannitol to hyaluronic acid-basedcompositions.

It is, moreover, known practice to add local anesthetics to fillingproducts in order to limit injection pain.

Certain patent applications and publications thus relate to hyaluronicacid-based compositions comprising lidocaine.

Application WO 93/12801 in the name of Reinmuller describes gels fortreating wounds and cheloid scars by subcutaneous injection. Example 1of said application relates to a composition based on hyaluronic acid of“hylagel” type (Biomatrix), and containing lidocaine.

The article by G. Wahl in Journal of Cosmetic Dermatology, relates tothe incorporation of lidocaine into filling compositions based onhyaluronic acid. The results presented relate to tests carried out usingJuvederm Ultra® which is a filling product based on crosslinkedhyaluronic acid. According to this article, more than 87% of patientshave indicated that they experience less pain during the injection ofcompositions incorporating lidocaine.

Application FR 2 979 539 in the name of Teoxane also discloses ahyaluronic acid-based composition comprising lidocaine.

Finally, a certain number of hyaluronic acid-based products comprisinglidocaine are sold, for example Juvederm®, Restylane®, EmervelLidocaine®, Teosyal Sense®, etc.

Anesthetics other than lidocaine are also used, for example a patentapplication EP 2 581 079 in the name of Biopolymer describescompositions based on hyaluronic acid and on prilocaine, which have aquick prilocaine release profile.

In application WO 2015/015407 In the name of Teoxane, compositions basedon non-crosslinked and partially crosslinked hyaluronic acid comprisingmepivacaine and lidocaine are disclosed.

In application EP 2 484 387 In the name of Q-Med, compositions based onhyaluronic acid and comprising a vitamin C derivative and also a localanesthetic are presented. In this application, the local anesthetic hasan effect of limiting the degradation of certain rheological propertiesduring autoclaving, while the vitamin C derivative has an oppositeeffect.

Local anesthetics are sometimes used in combination with polyols.

Hyaluronic acid-based compositions comprising both mannitol andlidocaine are sold; this is, for example, the case with the Stylage®products sold by Vivacy.

Application WO 2005/067994 in the name of Anika Therapeutics describeshyaluronic acid-based gels which comprise in particular lidocaine.Example 21 discloses that, on the compositions tested, lidocaine canhave an effect limiting the degradation of some rheological propertiesduring sterilization by moist heat (compared with the same sterilizedcomposition not comprising lidocaine).

In application WO 2010/015901 in the name of Allergan, and in particularin example 4, lidocaine is added to a certain number of compositionsbased on crosslinked hyaluronic acid. Whatever the hyaluronic acidcomposition, the addition of lidocaine does not have the effect ofimproving rheological properties during heat sterilization, but does nothowever have an effect of degradation of said rheological properties.

Application WO 2010/052430 in the name of Anteis describes a hyaluronicacid-based composition comprising a glycerol/sorbitol mixture and alsolidocaine. According to this application, the addition of lidocaine tocompositions already comprising a glycerol/sorbitol mixture has theeffect of limiting the degradation of the rheological properties of thecompositions during autoclaving.

In conclusion, the prior art discloses that the addition of exemplifiedpolyol(s) has the effect of limiting the degradation of the rheologicalproperties of a hyaluronic acid-based composition during heatsterilization. Moreover, the antioxidant properties of polyols allowbetter persistence in vivo, and these properties confer a certain numberof advantages on the compositions.

On the other hand, as regards lidocaine, the prior art disclosescontradictory effects, the consequence of adding lidocaine being eitherto limit the degradation, or to cause degradation of the rheologicalproperties, or to have few effects during heat sterilization.

As explained in the prior art, the addition of polyols is beneficial invivo. In particular, their antioxidant and free-radical-scavengingeffects are particularly beneficial, in particular for cells and DNAsequences. In addition, they improve the persistence of gels in vivo,and there is therefore a need for compositions comprising polyols.

Generally, the limitation of the degradation of some rheologicalproperties brought about by the addition of a polyol is known from theprior art, but can present a drawback for hyaluronic acid-basedcompositions intended to be injected, since their viscosity and/or theirviscoelastic properties may no longer be appropriate for thespecifications of the injectable products. In particular, injectiondifficulties can arise and the rheological properties can be toodifferent compared with those of the surrounding tissues.

As regards to the adaptation of the rheological properties with respectto those of the surrounding tissues, this makes it possible to limit theinflammatory phenomena and the feelings of discomfort and of thepresence of a foreign body.

There is therefore a need to obtain hyaluronic acid-based compositionswhich have all the properties associated with the addition of at leastone polyol, while at the same time making it possible to adapt theirrheological properties to the specifications of injectable products,during heat sterilization, in particular moist heat sterilization.

Surprisingly, the applicant has shown that the incorporation of at leastone local anesthetic, chosen from the group consisting of benzocaine,chloroprocaine, procaine, etidocaine, aptocaine, chlorobutanol,diamocaine, dyclonine, guafecainol, polidocanol, mepivacaine,prilocaine, articaine, bupivacaine, ropivacaine, tetracaine and saltsthereof and isolated isomers thereof, to a sterilized aqueouscomposition based on hyaluronic acid already comprising at least onepolyol has the effect of enabling the adaptation of the rheologicalproperties of the composition during sterilization, i.e. a reduction inthe elastic modulus G′, in the viscous modulus G″ and/or in theviscosity η.

This is particularly advantageous in the field of hyaluronic acid-basedinjectable compositions. Indeed, this makes it possible to obtaincompositions in which the rheological properties are close to those ofthe surrounding tissues.

This is particularly advantageous in the field of hyaluronic acid-basedinjectable compositions. Indeed, this makes it possible to obtaincompositions in which the rheology under low stress or at rest can beadapted to that of the surrounding tissues, which are resistant in vivo(by virtue in particular of the polyol(s)), and which do not cause anysignificant pain during injection (presence of at least one localanesthetic), which is a particularly appreciated and desired additionaleffect.

Finally, when the compositions according to the invention are confrontedwith high shear rates, found, for example:

-   -   during injection;    -   during friction of the skin once the composition has been        injected (having a wash, facial expressions, etc.);

they behave in a manner similar to the same compositions not comprisingthe at least one local anesthetic, which is also surprising. Thus, theinjectability is similar, and for example the facial expressions remainthe same as with a composition not comprising the at least one localanesthetic.

The term “hyaluronic acid” refers to crosslinked or non-crosslinkedhyaluronic acid, alone or as a mixture, optionally chemically modifiedby substitution, alone or as a mixture, optionally in the form of a saltthereof, alone or as a mixture.

The term “local anesthetic” refers to a local anesthetic or a saltthereof, alone or as a mixture.

Generally in the text of this application, the limits of a range ofvalues are included in this range, in particular in the expression“between . . . and . . . ”.

The term “Mw” or “molecular weight” refers to the weight-averagemolecular weight of the polymers, measured in Daltons.

In the present invention, the degree of crosslinking X is defined asbeing equal to the ratio:

$X = \frac{\begin{pmatrix}{{Number}\mspace{14mu} {of}\mspace{14mu} {moles}\mspace{14mu} {of}\mspace{14mu} {crosslinking}} \\{{agent}\mspace{14mu} {introduced}\mspace{14mu} {into}\mspace{14mu} {the}\mspace{14mu} {reaction}\mspace{14mu} {medium}}\end{pmatrix}}{\begin{pmatrix}{{Number}\mspace{14mu} {of}\mspace{14mu} {moles}\mspace{14mu} {of}\mspace{14mu} {disaccharide}} \\{{unit}\mspace{14mu} {introduced}\mspace{14mu} {into}\mspace{14mu} {the}\mspace{14mu} {reaction}\mspace{14mu} {medium}}\end{pmatrix}}$

The term “equivalent amount” refers to an amount equivalent in terms ofweight, or of moles or equivalent bioavailability.

The term “rheological properties” refers to the elastic modulus (G′),the viscous modulus (G″) and/or the dynamic viscosity (η).

The expression “degradation of the rheological properties during heatsterilization” refers to the reduction in value of the characteristicmeasured, compared with a composition not comprising the at least onepolyol and/or the at least one local anesthetic. The principlecharacteristics measured are the elastic modulus (G′), the viscositymodulus (G″) and/or the dynamic viscosity (η). When it is a question ofthe elastic modulus (G′, the value which decreases is that which isexpressed in Pa·s. When it is a question of the dynamic viscosity (η),the value which decreases is that which is expressed in Pa·s. When it isa question of the viscous modulus (G″), the value which decreases isthat which is expressed in Pa·s.

The term “injectability” refers to the ability of an injectablecomposition to be injected. Most commonly, the injectability isexpressed in Newtons (N) for injecting with a 27G1/2 needle with aplunger speed of 13 mm/minute. Good injectability results in a low force(N) and, conversely, the greater the force (N), the more difficult theinjectability is. The injectability can also be referred to as“extrusion force”.

The invention relates to an injectable sterilized aqueous compositioncomprising at least one hyaluronic acid, at least one polyol and atleast one local anesthetic chosen from the group consisting ofbenzocaine, chloroprocaine, procaine, etidocaine, aptocaine,chlorobutanol, diamocaine, dyclonine, guafecainol, polldocanol,mepivacaine, prilocaine, articaine, bupivacaine, ropivacaine, tetracaineand salts thereof and isolated isomers thereof.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chosen from the group consisting of benzocaine,chloroprocaine, procaine, etidocaine, aptocaine, diamocaine, dyclonine,guafecainol, mepivacaine, prilocaine, articaine, bupivacaine,ropivacaine, tetracaine and salts thereof and isolated isomers thereof.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chosen from the group consisting of benzocaine,chloroprocaine, procaine, etldocaine, aptocaine, diamocaine,mepivacaine, prilocaine, articaine, bupivacaine, ropivacaine, tetracaineand salts thereof and isolated isomers thereof.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chosen from the group consisting of benzocaine,chloroprocaine, procaine, etidocaine and salts thereof.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is benzocaine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chloroprocaine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is procaine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is etidocaine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chosen from the group consisting of aptocaine,chlorobutanol, diamocaine, dyclonine, guafecainol, polidocanol, andsalts thereof and isolated isomers thereof.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is aptocaine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chlorobutanol.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is diamocaine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is dyclonine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is guafecainol.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is polidocanol.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chosen from the group consisting of mepivacaine,prilocaine and salts thereof and isolated isomers thereof.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is mepivacaine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is prilocaine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chosen from the group consisting of articaine,bupivacaine, ropivacaine, tetracaine and salts thereof and isolatedisomers thereof.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is articaine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is bupivacaine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is ropivacaine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is tetracaine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises at least one non-crosslinkedhyaluronic acid or a salt thereof, alone or as a mixture.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises at least one crosslinked hyaluronicacid or a salt thereof, alone or as a mixture.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onecrosslinked hyaluronic acid has a degree of crosslinking X of between0.001 and 0.5.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onecrosslinked hyaluronic acid has a degree of crosslinking X of between0.01 and 0.4.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onecrosslinked hyaluronic acid has a degree of crosslinking X of between0.1 and 0.3.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onecrosslinked hyaluronic acid has a degree of crosslinking X of 0.06.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onecrosslinked hyaluronic acid has a degree of crosslinking X of 0.07.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onecrosslinked hyaluronic acid has a degree of crosslinking X of 0.12.

In one embodiment, the composition according to the invention ischaracterized in that the molecular weight Mw of the at least onehyaluronic acid is in a range between 0.01 MDa and 5 MDa.

In one embodiment, the composition according to the invention ischaracterized in that the molecular weight Mw of the at least onehyaluronic acid is in a range between 0.1 MDa and 3.5 MDa.

In one embodiment, the composition according to the invention ischaracterized in that the molecular weight Mw of the at least onehyaluronic acid is in a range between 1 MDa and 3 MDa.

In one embodiment, the composition according to the invention ischaracterized in that the molecular weight Mw of the at least onehyaluronic acid is in a range between 1 MDa and 2 MDa.

In one embodiment, the composition according to the invention ischaracterized in that the molecular weight Mw of the at least onehyaluronic acid is 1 MDa.

In one embodiment, the composition according to the invention ischaracterized in that the molecular weight Mw of the at least onehyaluronic acid is 2 MDa.

In one embodiment, the composition according to the invention ischaracterized in that the molecular weight Mw of the at least onehyaluronic acid is 3 MDa.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises at least one crosslinked ornon-crosslinked hyaluronic acid chemically modified by substitution, ora salt thereof, alone or as a mixture.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises at least one doubly crosslinkedhyaluronic acid as described in patent application WO 2000/046253 In thename of Fermentech Medical Limited.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises a mixture of crosslinked ornon-crosslinked hyaluronic acids or a salt thereof.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises a mixture of crosslinked hyaluronicacids or a salt thereof.

In one embodiment, the mixture of crosslinked hyaluronic acids or a saltthereof is a single-phase mixture such as the one described in patentapplication WO 2009/071697 in the name of the applicant.

In one embodiment, the mixture of crosslinked hyaluronic acids or a saltthereof is a mixture obtained by mixing several hyaluronic acids, or asalt thereof, of different molecular weights prior to theircrosslinking, as described in patent application WO 2004/092222 in thename of Cornéal Industrie.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises at least one hyaluronic acid, or asalt thereof, substituted with a group providing lipophilic or hydratingproperties, for instance the substituted hyaluronic acids as describedin patent application FR 2 983 483 In the name of the applicant.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that at least onehyaluronic acid is in the form of a sodium salt or of a potassium salt.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises at least one co-crosslinkedhyaluronic acid or a salt thereof, alone or as a mixture.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid [HA] is between 2 mg/g and 50 mg/g oftotal weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid [HA] is between 4 mg/g and 40 mg/g oftotal weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid [HA] is between 5 mg/g and 30 mg/g oftotal weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid [HA] is between 10 mg/g and 30 mg/g oftotal weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid [HA] is 20 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid is between 0.2% and 5% by weightrelative to the total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid is greater than or equal to 1% byweight relative to the total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is chosen from the group consisting of glycerol, sorbitol,propylene glycol, xylitol, mannitol, erythritol, maltitol and lactitol,alone or as mixture.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is chosen from the group consisting of mannitol, sorbitol,maltitol and glycerol, alone or as a mixture.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is chosen from the group consisting of mannitol, sorbitol andmaltitol, alone or as a mixture.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is mannitol.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is sorbitol.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is maltitol.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is glycerol.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises at least mannitol and sorbitol.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises at least mannitol and maltitol.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 0.01 mg/g and 50 mg/g.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 10 and 40 mg/g of total weightof said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 15 and 30 mg/g of total weightof said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 15 and 25 mg/g of total weightof said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 20 and 40 mg/g of total weightof said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 20 and 30 mg/g of total weightof said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 25 and 35 mg/g of total weightof said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is 35 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is mannitol and the concentration thereof is between 10 and 40mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is mannitol and the concentration thereof is between 15 and 30mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is mannitol and the concentration thereof is between 15 and 25mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is mannitol and the concentration thereof is between 20 and 40mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is mannitol and the concentration thereof is between 25 and 35mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is mannitol and the concentration thereof is 35 mg/g of totalweight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is sorbitol and the concentration thereof is between 10 and 40mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is sorbitol and the concentration thereof is between 15 and 30mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is sorbitol and the concentration thereof is between 15 and 25mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is sorbitol and the concentration thereof is between 20 and 40mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is sorbitol and the concentration thereof is between 25 and 35mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is sorbitol and the concentration thereof is 35 mg/g of totalweight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is maltitol and the concentration thereof is between 10 and 40mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is maltitol and the concentration thereof is between 15 and 30mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is maltitol and the concentration thereof is between 15 and 25mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is maltitol and the concentration thereof is between 20 and 40mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is maltitol and the concentration thereof is between 25 and 35mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is maltitol and the concentration thereof is 35 mg/g of totalweight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is glycerol and the concentration thereof is between 10 and 40mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is glycerol and the concentration thereof is between 15 and 30mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is glycerol and the concentration thereof is between 15 and 25mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is glycerol and the concentration thereof is between 20 and 40mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is glycerol and the concentration thereof is between 25 and 35mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onepolyol is glycerol and the concentration thereof is 35 mg/g of totalweight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 0.01 mg/g and 50 mg/gof total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 0.05 mg/g and 45 mg/gof total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 0.1 mg/g and 40 mg/gof total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 0.2 mg/g and 30 mg/gof total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 0.5 mg/g and 20 mg/gof total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 1 mg/g and 15 mg/g oftotal weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 1 mg/g and 10 mg/g oftotal weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 1 mg/g and 6 mg/g oftotal weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 1 mg/g and 5 mg/g oftotal weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 2 mg/g and 5 mg/g oftotal weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 6 mg/g and 10 mg/g oftotal weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is 1 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is 4 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is 5 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is 10 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is benzocaine [BENZ], and wherein the concentration ofbenzocaine [BENZ] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is benzocaine [BENZ], and wherein the concentration ofbenzocaine [BENZ] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is benzocaine [BENZ], and wherein the concentration ofbenzocaine [BENZ] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is benzocaine [BENZ], and wherein the concentration ofbenzocaine [BENZ] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chloroprocaine [CHPR], and wherein the concentrationof chloroprocaine [CHPR] is between 0.01 mg/g and 50 mg/g of totalweight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chloroprocaine [CHPR], and wherein the concentrationof chloroprocaine [CHPR] is between 1 mg/g and 15 mg/g of total weightof said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chloroprocaine [CHPR], and wherein the concentrationof chloroprocaine [CHPR] is between 1 mg/g and 6 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chloroprocaine [CHPR], and wherein the concentrationof chloroprocaine [CHPR] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is procaine [PROC], and wherein the concentration ofprocaine [PROC] is between 0.01 mg/g and 50 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is procaine [PROC], and wherein the concentration ofprocaine [PROC] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is procaine [PROC], and wherein the concentration ofprocaine [PROC] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is procaine [PROC], and wherein the concentration ofprocaine [PROC] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is etidocaine [ETID], and wherein the concentration ofetidocaine [ETID] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is etidocaine [ETID], and wherein the concentration ofetidocaine [ETID] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is etidocaine [ETID], and wherein the concentration ofetidocaine [ETID] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is etidocaine [ETID], and wherein the concentration ofetidocaine [ETID] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is aptocaine [APTO], and wherein the concentration ofaptocaine [APTO] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is aptocaine [APTO], and wherein the concentration ofaptocaine [APTO] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is aptocaine [APTO], and wherein the concentration ofaptocaine [APTO] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is aptocaine [APTO], and wherein the concentration ofaptocaine [APTO] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chlorobutanol [CHLO], and wherein the concentrationof chlorobutanol [CHLO] is between 0.01 mg/g and 50 mg/g of total weightof said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chlorobutanol [CHLO], and wherein the concentrationof chlorobutanol [CHLO] is between 1 mg/g and 15 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chlorobutanol [CHLO], and wherein the concentrationof chlorobutanol [CHLO] is between 1 mg/g and 6 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is chlorobutanol [CHLO], and wherein the concentrationof chlorobutanol [CHLO] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is diamocaine [DIAM], and wherein the concentration ofdiamocaine [DIAM] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is diamocaine [DIAM], and wherein the concentration ofdiamocaine [DIAM] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is diamocaine [DIAM], and wherein the concentration ofdiamocaine [DIAM] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is diamocaine [DIAM], and wherein the concentration ofdiamocaine [DIAM] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is dyclonine [DYCL], and wherein the concentration ofdyclonine [DYCL] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is dyclonine [DYCL], and wherein the concentration ofdyclonine [DYCL] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is dyclonine [DYCL], and wherein the concentration ofdyclonine [DYCL] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is dyclonine [DYCL], and wherein the concentration ofdyclonine [DYCL] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is guafecainol [GUAF], and wherein the concentration ofguafecainol [GUAF] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is guafecainol [GUAF], and wherein the concentration ofguafecainol [GUAF] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is guafecainol [GUAF], and wherein the concentration ofguafecainol [GUAF] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is guafecainol [GUAF], and wherein the concentration ofguafecainol [GUAF] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is polidocanol [POLI], and wherein the concentration ofpolidocanol [POLI] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is polidocanol [POLI], and wherein the concentration ofpolidocanol [POLI] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is polidocanol [POLI], and wherein the concentration ofpolidocanol [POLI] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is polidocanol [POLI], and wherein the concentration ofpolidocanol [POLI] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is mepivacaine [MEPI], and wherein the concentration ofmepicavaine [MEPI] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is mepivacaine [MEPI], and wherein the concentration ofmepicavaine [MEPI] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is mepivacaine [MEPI], and wherein the concentration ofmepicavaine [MEPI] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is mepivacaine [MEPI], and wherein the concentration ofmepicavaine [MEPI] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is prilocaine [PRILO], and wherein the concentration ofprilocaine [PRILO] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is prilocaine [PRILO], and wherein the concentration ofprilocaine [PRILO] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is prilocaine [PRILO], and wherein the concentration ofprilocaine [PRILO] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is prilocaine [PRILO], and wherein the concentration ofprilocaine [PRILO] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is articaine [ARTI], and wherein the concentration ofarticaine [ARTI] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is articaine [ARTI], and wherein the concentration ofarticaine [ARTI] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is articaine [ARTI], and wherein the concentration ofarticaine [ARTI] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is articaine [ARTI], and wherein the concentration ofarticaine [ARTI] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is bupivacaine [BUPI], and wherein the concentration ofbupivacaine [BUPI] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is bupivacaine [BUPI], and wherein the concentration ofbupivacaine [BUPI] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is bupivacaine [BUPI], and wherein the concentration ofbupivacaine [BUPI] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is bupivacaine [BUPI], and wherein the concentration ofbupivacaine [BUPI] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is ropivacaine [ROPI], and wherein the concentration ofropivacaine [ROPI] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is ropivacaine [ROPI], and wherein the concentration ofropivacaine [ROPI] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is ropivacaine [ROPI], and wherein the concentration ofropivacaine [ROPI] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is ropivacaine [ROPI], and wherein the concentration ofropivacaine [ROPI] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is tetracaine [TETRA], and wherein the concentration oftetracaine [TETRA] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is tetracaine [TETRA], and wherein the concentration oftetracaine [TETRA] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is tetracaine [TETRA], and wherein the concentration oftetracaine [TETRA] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is tetracaine [TETRA], and wherein the concentration oftetracaine [TETRA] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the composition according to the invention ischaracterized in that the weight ratio between the concentration of theat least one polyol [Po] and the concentration of the at least one localanesthetic [AL]:[Po]/[AL] is between 0.0002 and 5000;0.0002≤[Po]/[AL]≤5000.

In one embodiment, the composition according to the invention ischaracterized in that the weight ratio between the concentration of theat least one polyol [Po] and the concentration of the at least one localanesthetic [AL]:[Po]/[AL] is between 0.002 and 500; 0.002≤[Po]/[AL]≤500.

In one embodiment, the composition according to the invention ischaracterized in that the weight ratio between the concentration of theat least one polyol [Po] and the concentration of the at least one localanesthetic [AL]:[Po]/[AL] is between 0.02 and 50; 0.02≤[Po]/[AL]≤50.

In one embodiment, the composition according to the invention ischaracterized in that the weight ratio between the concentration of theat least one polyol [Po] and the concentration of the at least one localanesthetic [AL]:[Po]/[AL] is between 1 and 20; 1≤[Po]/[AL]≤20.

In one embodiment, the composition according to the invention ischaracterized in that the weight ratio between the concentration of theat least one polyol [Po] and the concentration of the at least one localanesthetic [AL]:[Po]/[AL] is between 3 and 15; 3≤[Po]/[AL]≤15.

In one embodiment, the composition according to the invention ischaracterized in that the weight ratio between the concentration of theat least one polyol [Po] and the concentration of the at least one localanesthetic [AL]:[Po]/[AL] is between 4 and 8; 4≤[Po]/[AL]≤8.

In one embodiment, the composition according to the invention ischaracterized in that the weight ratio between the concentration of theat least one polyol [Po] and the concentration of the at least one localanesthetic [AL]:[Po]/[AL] is between 10 and 13; 10≤[Po]/[AL]≤13.

In one embodiment, the composition according to the invention ischaracterized in that the weight ratio between the concentration of theat least one hyaluronic acid [HA] and the concentration of the at leastone local anesthetic [AL]:[HA]/[AL] is between 0.1 and 50;0.1≤[HA]/[AL]≤50.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 0.5 and 40; 0.5≤[HA]/[AL]≤40.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 1 and 30; 1≤[HA]/[AL]≤30.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 2 and 20; 2≤[HA]/[AL]≤20.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 7/3 and 26/3; 7/3≤[HA]/[AL]≤26/3.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 2 and 20/3; 2≤[HA]/[AL]≤20/3.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 2 and 10/3; 2≤[HA]/[AL]≤10/3.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] is20.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] is26/3.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic add [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] is20/3.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] is10/3.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] is7/3.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] is2.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the sterilization iscarried out by heat, moist heat, gamma (γ) radiation, or by acceleratedelectron beam.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the sterilizationstep is carried out by heat.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the sterilizationstep is carried out by steam autoclaving.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the sterilization bysteam autoclaving is carried out at a temperature of 121 to 134° C., fora time adapted to time adapted to the temperature.

For example, the sterilization by steam autoclaving is carried out at atemperature of between 127 and 130° C. for a period of between 1 and 20min.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the sterilizationstep is carried out by irradiation with gamma (γ) radiation.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention further comprises at least one additionalcompound.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one additional compound [CA] is between 0.1 and 100 mg/g oftotal weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one additional compound [CA] is between 1 and 50 mg/g oftotal weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least oneadditional compound is dimethyl sulfone, hereinafter DMS.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least oneadditional compound is a water-soluble salt of sucrose octasulfate,hereinafter SOS.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least oneadditional compound is a vitamin C derivative.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least oneadditional compound is a salt of magnesium ascorbyl phosphate,hereinafter MAP.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least oneadditional compound belongs to the catecholamine family.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least oneadditional compound belonging to the catecholamine family isepinephrine.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one additional compound [CA] is between 0.01% and 10% byweight relative to the total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the concentration ofthe at least one additional compound [CA] is between 0.1% and 5% byweight relative to the total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least oneadditional compound is dimethyl sulfone and the concentration thereof isbetween 1 and 10 mg/g of total weight of said composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least oneadditional compound is a water-soluble salt of sucrose octasulfate andthe concentration thereof is between 1 and 40 mg/g of total weight ofsaid composition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least oneadditional compound is a salt of magnesium ascorbyl phosphate and theconcentration thereof is between 0.3 and 20 mg/g of total weight of saidcomposition.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention is characterized in that the at least onelocal anesthetic is freely released in vivo.

The invention also relates to a process for adapting the rheologicalproperties of a sterilized injectable aqueous composition comprising atleast one hyaluronic acid and at least one polyol, which comprises theaddition to said composition, before the sterilization step, of at leastone local anesthetic chosen from the group consisting of benzocaine,chloroprocaine, procaine, etidocaine, aptocaine, chlorobutanol,diamocaine, dyclonine, guafecainol, polidocanol, mepivacaine,prilocaine, articaine, bupivacaine, ropivacaine, tetracaine and saltsthereof and isolated isomers thereof.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chosen from the group consisting of benzocaine,chloroprocaine, procaine, etidocaine, aptocaine, diamocaine, dyclonine,guafecainol, mepivacaine, prilocaine, articaine, bupivacaine,ropivacaine, tetracaine and salts thereof and isolated isomers thereof.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chosen from the group consisting of benzocaine,chloroprocaine, procaine, etidocaine, aptocaine, diamocaine,mepivacaine, prilocaine, articaine, bupivacaine, ropivacaine, tetracaineand salts thereof and isolated isomers thereof.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chosen from the group consisting of benzocaine,chloroprocaine, procaine, etidocaine and salts thereof.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is benzocaine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chloroprocaine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is procaine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is etidocaine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chosen from the group consisting of aptocaine,chlorobutanol, diamocaine, dyclonine, guafecainol, polidocanol, andsalts thereof and isolated isomers.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is aptocaine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chlorobutanol.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is diamocaine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is dyclonine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is guafecainol.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is polidocanol.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chosen from the group consisting of mepivacaine,prilocaine and salts thereof and isolated isomers thereof.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is mepivacaine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is prilocaine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chosen from the group consisting of articaine,bupivacaine, ropivacaine, tetracaine and salts thereof and isolatedisomers thereof.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is articaine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is bupivacaine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is ropivacaine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is tetracaine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onehyaluronic acid is a non-crosslinked hyaluronic acid or a salt thereof,alone or as a mixture.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onehyaluronic acid is a crosslinked hyaluronic acid or a salt thereof,alone or as a mixture.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onecrosslinked hyaluronic acid has a degree of crosslinking X of between0.001 and 0.5.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onecrosslinked hyaluronic acid has a degree of crosslinking X of between0.01 and 0.4.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onecrosslinked hyaluronic acid has a degree of crosslinking X of between0.1 and 0.3.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onecrosslinked hyaluronic acid has a degree of crosslinking X of 0.06.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onecrosslinked hyaluronic acid has a degree of crosslinking X of 0.07.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onecrosslinked hyaluronic acid has a degree of crosslinking X of 0.12.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the molecular weightMw of the at least one hyaluronic acid is in a range between 0.01 MDaand 5 MDa.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the molecular weightMw of the at least one hyaluronic acid is in a range between 0.1 MDa and3.5 MDa.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the molecular weightMw of the at least one hyaluronic acid is in a range between 1 MDa and 3MDa.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the molecular weightMw of the at least one hyaluronic acid is in a range between 1 MDa and 2MDa.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the molecular weightMw of the at least one hyaluronic acid is 1 MDa.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the molecular weightMw of the at least one hyaluronic acid is 2 MDa.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the molecular weightMw of the at least one hyaluronic acid is 3 MDa.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that said compositioncomprises at least one crosslinked or non-crosslinked hyaluronic acidchemically modified by substitution, or a salt thereof, alone or as amixture.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises at least one doubly crosslinkedhyaluronic acid as described in patent application WO 2000/046253 In thename of Fermentech Medical Limited.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises a mixture of crosslinked andnon-crosslinked hyaluronic acids or a salt thereof.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises a mixture of crosslinked hyaluronicacids or a salt thereof.

In one embodiment, the mixture of crosslinked hyaluronic acids or a saltthereof is a single-phase mixture such as the one described in patentapplication WO 2009/071697 in the name of the applicant.

In one embodiment, the mixture of crosslinked hyaluronic acids or a saltthereof is a mixture obtained by mixing several hyaluronic adds, or asalt thereof, of different molecular weights prior to theircrosslinking, as described in patent application WO 2004/092222 In thename of Cornéal Industrie.

In one embodiment, the injectable sterilized aqueous compositionaccording to the invention comprises at least one hyaluronic acid, or asalt thereof, substituted with a group providing lipophilic or hydratingproperties, for instance the substituted hyaluronic acids as describedin patent application FR 2 983 483 in the name of the applicant.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that at least onehyaluronic acid is in the form of a sodium salt or of a potassium salt.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onehyaluronic acid is a co-crosslinked hyaluronic acid or a salt thereof,alone or as a mixture.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid [HA] is between 2 mg/g and 50 mg/g oftotal weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid [HA] is between 4 mg/g and 40 mg/g oftotal weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid [HA] is between 5 mg/g and 30 mg/g oftotal weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid [HA] is between 10 mg/g and 30 mg/g oftotal weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onehyaluronic acid [HA] is 20 mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid is between 0.2% and 5% by weightrelative to the total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid is greater than or equal to 1% byweight relative to the total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one hyaluronic acid [HA] is 20 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is chosen from the group consisting of glycerol, sorbitol,propylene glycol, xylitol, mannitol, erythritol, maltitol and lactitol,alone or as a mixture.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is chosen from the group consisting of mannitol, sorbitol,maltitol and glycerol, alone or as a mixture.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is chosen from the group consisting of mannitol, sorbitol andmaltitol, alone or as a mixture.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is mannitol.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is sorbitol.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is maltitol.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is glycerol.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that said compositioncomprises at least mannitol and sorbitol.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that said compositioncomprises at least mannitol and maltitol.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 0.01 mg/g and 50 mg/g.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 10 and 40 mg/g of total weightof said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 15 and 30 mg/g of total weightof said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 15 and 25 mg/g of total weightof said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 20 and 40 mg/g of total weightof said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 20 and 30 mg/g of total weightof said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is between 25 and 35 mg/g of total weightof said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one polyol [Po] is 35 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is mannitol and the concentration thereof is between 10 and 40mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is mannitol and the concentration thereof is between 15 and 30mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is mannitol and the concentration thereof is between 15 and 25mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is mannitol and the concentration thereof is between 20 and 40mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is mannitol and the concentration thereof is between 25 and 35mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is mannitol and the concentration thereof is 35 mg/g of totalweight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is sorbitol and the concentration thereof is between 10 and 40mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is sorbitol and the concentration thereof is between 15 and 30mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is sorbitol and the concentration thereof is between 15 and 25mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is sorbitol and the concentration thereof is between 20 and 40mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is sorbitol and the concentration thereof is between 25 and 35mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is sorbitol and the concentration thereof is 35 mg/g of totalweight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is maltitol and the concentration thereof is between 10 and 40mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is maltitol and the concentration thereof is between 15 and 30mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is maltitol and the concentration thereof is between 15 and 25mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is maltitol and the concentration thereof is between 20 and 40mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is maltitol and the concentration thereof is between 25 and 35mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is maltitol and the concentration thereof is 35 mg/g of totalweight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is glycerol and the concentration thereof is between 10 and 40mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is glycerol and the concentration thereof is between 15 and 30mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is glycerol and the concentration thereof is between 15 and 25mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is glycerol and the concentration thereof is between 20 and 40mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is glycerol and the concentration thereof is between 25 and 35mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onepolyol is glycerol and the concentration thereof is 35 mg/g of totalweight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 0.01 mg/g and 50 mg/gof total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 0.05 mg/g and 45 mg/gof total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 0.1 mg/g and 40 mg/gof total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 0.2 mg/g and 30 mg/gof total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 0.5 mg/g and 20 mg/gof total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 1 mg/g and 15 mg/g oftotal weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 1 mg/g and 10 mg/g oftotal weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 1 mg/g and 6 mg/g oftotal weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 1 mg/g and 5 mg/g oftotal weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 2 mg/g and 5 mg/g oftotal weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is between 6 mg/g and 10 mg/g oftotal weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is 1 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is 4 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is 5 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one local anesthetic [AL] is 10 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is benzocaine [BENZ], and wherein the concentration ofbenzocaine [BENZ] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is benzocaine [BENZ], and wherein the concentration ofbenzocaine [BENZ] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is benzocaine [BENZ], and wherein the concentration ofbenzocaine [BENZ] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is benzocaine [BENZ], and wherein the concentration ofbenzocaine [BENZ] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chloroprocaine [CHPR], and wherein the concentrationof chloroprocaine [CHPR] is between 0.01 mg/g and 50 mg/g of totalweight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chloroprocaine [CHPR], and wherein the concentrationof chloroprocaine [CHPR] is between 1 mg/g and 15 mg/g of total weightof said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chloroprocaine [CHPR], and wherein the concentrationof chloroprocaine [CHPR] is between 1 mg/g and 6 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chloroprocaine [CHPR], and wherein the concentrationof chloroprocaine [CHPR] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is procaine [PROC], and wherein the concentration ofprocaine [PROC] is between 0.01 mg/g and 50 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is procaine [PROC], and wherein the concentration ofprocaine [PROC] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is procaine [PROC], and wherein the concentration ofprocaine [PROC] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is procaine [PROC], and wherein the concentration ofprocaine [PROC] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is etidocaine [ETID], and wherein the concentration ofetidocaine [ETID] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is etidocaine [ETID], and wherein the concentration ofetidocaine [ETID] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is etidocaine [ETID], and wherein the concentration ofetidocaine [ETID] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is etidocaine [ETID], and wherein the concentration ofetidocaine [ETID] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is aptocaine [APTO], and wherein the concentration ofaptocaine [APTO] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is aptocaine [APTO], and wherein the concentration ofaptocaine [APTO] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is aptocaine [APTO], and wherein the concentration ofaptocaine [APTO] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is aptocaine [APTO], and wherein the concentration ofaptocaine [APTO] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chlorobutanol [CHLO], and wherein the concentrationof chlorobutanol [CHLO] is between 0.01 mg/g and 50 mg/g of total weightof said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chlorobutanol [CHLO], and wherein the concentrationof chlorobutanol [CHLO] is between 1 mg/g and 15 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chlorobutanol [CHLO], and wherein the concentrationof chlorobutanol [CHLO] is between 1 mg/g and 6 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is chlorobutanol [CHLO], and wherein the concentrationof chlorobutanol [CHLO] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is diamocaine [DIAM], and wherein the concentration ofdiamocaine [DIAM] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is diamocaine [DIAM], and wherein the concentration ofdiamocaine [DIAM] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is diamocaine [DIAM], and wherein the concentration ofdiamocaine [DIAM] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is diamocaine [DIAM], and wherein the concentration ofdiamocaine [DIAM] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is dyclonine [DYCL], and wherein the concentration ofdyclonine [DYCL] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is dyclonine [DYCL], and wherein the concentration ofdyclonine [DYCL] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is dyclonine [DYCL], and wherein the concentration ofdyclonine [DYCL] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is dyclonine [DYCL], and wherein the concentration ofdyclonine [DYCL] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is guafecainol [GUAF], and wherein the concentration ofguafecainol [GUAF] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is guafecainol [GUAF], and wherein the concentration ofguafecainol [GUAF] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is guafecainol [GUAF], and wherein the concentration ofguafecainol [GUAF] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is guafecainol [GUAF], and wherein the concentration ofguafecainol [GUAF] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is polidocanol [POLI], and wherein the concentration ofpolidocanol [POLI] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is polidocanol [POLI], and wherein the concentration ofpolidocanol [POLI] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is polidocanol [POLI], and wherein the concentration ofpolldocanol [POLI] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is polidocanol [POLI], and wherein the concentration ofpolidocanol [POLI] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is mepivacaine [MEPI], and wherein the concentration ofmepivacaine [MEPI] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is mepivacaine [MEPI], and wherein the concentration ofmepivacaine [MEPI] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is mepivacaine [MEPI], and wherein the concentration ofmepivacaine [MEPI] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is mepivacaine [MEPI], and wherein the concentration ofmepivacaine [MEPI] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is prilocaine [PRILO], and wherein the concentration ofprilocaine [PRILO] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is prilocaine [PRILO], and wherein the concentration ofprilocaine [PRILO] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is prilocaine [PRILO], and wherein the concentration ofprilocaine [PRILO] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is prilocaine [PRILO], and wherein the concentration ofprilocaine [PRILO] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is articaine [ARTI], and wherein the concentration ofarticaine [ARTI] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is articaine [ARTI], and wherein the concentration ofarticaine [ARTI] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is articaine [ARTI], and wherein the concentration ofarticaine [ARTI] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is articaine [ARTI], and wherein the concentration ofarticaine [ARTI] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is bupivacaine [BUPI], and wherein the concentration ofbupivacaine [BUPI] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is bupivacaine [BUPI], and wherein the concentration ofbupivacaine [BUPI] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is bupivacaine [BUPI], and wherein the concentration ofbupivacaine [BUPI] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is bupivacaine [BUPI], and wherein the concentration ofbupivacaine [BUPI] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is ropivacaine [ROPI], and wherein the concentration ofropivacaine [ROPI] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is ropivacaine [ROPI], and wherein the concentration ofropivacaine [ROPI] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is ropivacaine [ROPI], and wherein the concentration ofropivacaine [ROPI] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is ropivacaine [ROPI], and wherein the concentration ofropivacaine [ROPI] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is tetracaine [TETRA], and wherein the concentration oftetracaine [TETRA] is between 0.01 mg/g and 50 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is tetracaine [TETRA], and wherein the concentration oftetracaine [TETRA] is between 1 mg/g and 15 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is tetracaine [TETRA], and wherein the concentration oftetracaine [TETRA] is between 1 mg/g and 6 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is tetracaine [TETRA], and wherein the concentration oftetracaine [TETRA] is approximately 3 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one polyol [Po] and theconcentration of the at least one local anesthetic [AL]:[Po]/[AL] isbetween 0.0002 and 5000; 0.0002≤[Po]/[AL]≤5000.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one polyol [Po] and theconcentration of the at least one local anesthetic [AL]:[Po]/[AL] isbetween 0.002 and 500; 0.002≤[Po]/[AL]≤500.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one polyol [Po] and theconcentration of the at least one local anesthetic [AL]:[Po]/[AL] isbetween 0.02 and 50; 0.02≤[Po]/[AL]≤50.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one polyol [Po] and theconcentration of the at least one local anesthetic [AL]:[Po]/[AL] isbetween 1 and 20; 1≤[Po]/[AL]≤20.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one polyol [Po] and theconcentration of the at least one local anesthetic [AL]:[Po]/[AL] isbetween 3 and 15; 3≤[Po]/[AL]≤15.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one polyol [Po] and theconcentration of the at least one local anesthetic [AL]:[Po]/[AL] isbetween 4 and 8; 4≤[Po]/[AL]≤8.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one polyol [Po] and theconcentration of the at least one local anesthetic [AL]:[Po]/[AL] isbetween 10 and 13; 10≤[Po]/[AL]≤13.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic add [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 0.1 and 50; 0.1≤[HA]/[AL]≤50.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 0.5 and 40; 0.5≤[HA]/[AL]≤40.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 1 and 30; 1≤[HA]/[AL]≤30.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 2 and 20; 2≤[HA]/[AL]≤20.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 7/3 and 26/3; 7/3≤[HA]/[AL]≤26/3.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 2 and 20/3; 2≤[HA]/[AL]≤20/3.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] isbetween 2 and 10/3; [HA]/[AL]≤10/3.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] is20.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] is26/3.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic add [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] is20/3.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic add [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] is10/3.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] is7/3.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the weight ratiobetween the concentration of the at least one hyaluronic acid [HA] andthe concentration of the at least one local anesthetic [AL]:[HA]/[AL] is2.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the sterilizationstep is carried out by heat, moist heat, gamma (γ), radiation, or byaccelerated electron beam.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the sterilizationstep is carried out by steam autoclaving.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the sterilization bysteam autoclaving is carried out at a temperature of 121 to 134° C., fora time adapted to the temperature.

For example, the sterilization by steam autoclaving is carried out at atemperature of between 127 and 130° C. for a period of between 1 and 20min.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the sterilizationstep is carried out by irradiation with gamma (γ) radiation.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that said compositionfurther comprises at least one additional compound.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one additional compound [CA] is between 0.1 and 100 mg/g oftotal weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one additional compound [CA] is between 1 and 50 mg/g oftotal weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least oneadditional compound is dimethyl sulfone, hereinafter DMS.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least oneadditional compound is a water-soluble salt of sucrose octasulfate,hereinafter SOS.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least oneadditional compound is a vitamin C derivative.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least oneadditional compound is a salt of magnesium ascorbyl phosphate,hereinafter MAP.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least oneadditional compound belongs to the catecholamine family.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least oneadditional compound belonging to the catecholamine family isepinephrine.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one additional compound [CA] is between 0.01% and 10% byweight relative to the total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the concentration ofthe at least one additional compound [CA] is between 0.1% and 5% byweight relative to the total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least oneadditional compound is dimethyl sulfone and the concentration thereof isbetween 1 and 10 mg/g of total weight of said composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least oneadditional compound is a water-soluble salt of sucrose octasulfate andthe concentration thereof is between 1 and 40 mg/g of total weight ofsaid composition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least oneadditional compound is a salt of magnesium ascorbyl phosphate and theconcentration thereof is between 0.3 and 20 mg/g of total weight of saidcomposition.

In one embodiment, the process for adapting the rheological propertiesaccording to the invention is characterized in that the at least onelocal anesthetic is freely released in vivo.

The invention also relates to a process for producing an injectablesterilized aqueous composition according to the invention, whichcomprises at least the following steps:

-   -   1) a step of hydration in a buffer solution at a pH close to        physiological pH of the fibers of at least one hyaluronic acid        or a salt thereof, alone or as a mixture, so as to obtain a        hydrogel;    -   2) a step of incorporation of at least one polyol in aqueous        solution into the hydrogel obtained in the previous step;    -   3) a step of incorporation of at least one local anesthetic        chosen from the group consisting of benzocaine, chloroprocaine,        procaine, etidocaine, aptocaine, chlorobutanol, diamocaine,        dyclonine, guafecainol, polidocanol, mepivacaine, prilocaine,        articaine, bupivacaine, ropivacaine and tetracaine and salts        thereof and isolated isomers thereof, into the hydrogel obtained        in the previous step;    -   4) a homogenization step; and    -   5) a sterilization step;        it being possible for said steps 2) and 3) to be carried out in        any order or simultaneously.

In one embodiment, the process according to the invention ischaracterized in that the at least one local anesthetic is incorporatedin solid form.

In one embodiment, the process according to the invention ischaracterized in that the at least one local anesthetic is incorporatedin powder form.

In one embodiment, the process according to the invention ischaracterized in that the at least one local anesthetic is incorporatedin the form of the solution.

In one embodiment, the process according to the invention ischaracterized in that the hyaluronic acid is in the form of fibers.

In one embodiment, the process according to the invention ischaracterized in that the hyaluronic acid is in the form of paillettes.

In one embodiment, the process according to the invention ischaracterized in that the buffer solution is an aqueous solution ofphosphate buffer.

In one embodiment, the process according to the invention ischaracterized in that the pH of the solution of at least one localanesthetic is adjusted to a value of between 6.5 and 7 before it isintroduced into the gel and/or hydrogel.

In one embodiment, the process according to the invention ischaracterized in that the pH of the gel and/or hydrogel is adjusted to avalue of between 7.7 and 8 before the incorporation of at least onelocal anesthetic, the pH of which is not adjusted.

In one embodiment, the process according to the invention ischaracterized in that the solution of at least one local anesthetic isincorporated into the gel according to the process described in patentapplication WO 2010/015901 in the name of Allergan.

In one embodiment, the process according to the invention ischaracterized in that the hydration step is carried out at ambienttemperature.

In one embodiment, the process according to the invention ischaracterized in that the homogenization step is carried out at ambienttemperature.

In one embodiment, the process according to the invention furthercomprises at least one step of packaging the homogenized mixture insyringes.

In one embodiment, the process according to the invention furthercomprises at least one step of packaging the homogenized mixture insingle-dose bottles.

In one embodiment, the process according to the invention comprises atleast one sterilization step.

In one embodiment, the process according to the invention ischaracterized in that the sterilization step is carried out after thepackaging step.

In one embodiment, the process according to the invention ischaracterized in that the sterilization step is carried out by heat,moist heat, gamma (γ) radiation or by accelerated electron beam.

In one embodiment, the process according to the invention ischaracterized in that said sterilization step is carried out by heat.

In one embodiment, the process according to the invention is one inwhich said sterilization step is carried out by steam autoclaving.

In one embodiment, the process according to the invention ischaracterized in that said sterilization step is carried out after thepackaging by steam autoclaving.

In one embodiment, the process according to the invention ischaracterized in that said sterilization step is carried out after thepackaging, by irradiation with gamma (γ) radiation or by acceleratedelectron beam.

In one embodiment, the process according to the invention ischaracterized in that the sterilization by steam autoclaving is carriedout after the packaging, at a temperature of 121 to 134° C., for a timeadapted to the temperature.

For example, the sterilization by steam autoclaving is carried out at atemperature of between 127 and 130° C. for a period of between 1 and 20min.

In one embodiment, the process according to the invention furthercomprises at least one crosslinking step.

In one embodiment, the process according to the invention furthercomprises at least one crosslinking step simultaneously with orsubsequent to step 1.

In one embodiment, the process according to the invention furthercomprises at least one crosslinking step simultaneously with step 1.

In one embodiment, the process according to the invention furthercomprises at least one crosslinking step subsequent to step 1.

In one embodiment, the process according to the invention ischaracterized in that at least one crosslinking step lies between thehydration step and the step of incorporating at least one localanesthetic.

In one embodiment, the process according to the invention ischaracterized in that at least one crosslinking step is carried out bymeans of at least one crosslinking agent.

In one embodiment, the process according to the invention ischaracterized in that the at least one crosslinking agent isbifunctional or polyfunctional.

In one embodiment, the process according to the invention ischaracterized in that the at least one bifunctional or polyfunctionalcrosslinking agent is chosen from the group consisting of ethyleneglycol diglycidyl ether, butanediol diglycidyl ether (BDDE),polyglycerol polyglycidyl ether, polyethylene glycol diglycidyl ether,polypropylene glycol diglycidyl ether, a bis- or polyepoxy such as1,2,3,4-diepoxybutane or 1,2,7,8-diepoxyoctane, a dialkyl sulfone,divinyl sulfone, formaldehyde, epichlorohydrin or else glutaraldehyde,and carbodiimides such as, for example,1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC).

In one embodiment, the process according to the invention ischaracterized in that the at least one bifunctional crosslinking agentis butanediol diglycidyl ether (BDDE) or 1,2,7,8-diepoxyoctane.

In one embodiment, the production process according to the invention ischaracterized in that the crosslinking step is carried out according tothe techniques known to those skilled in the art.

In one embodiment, the process according to the invention comprises,after the crosslinking step, at least one purification and washing stepcarried out according to the techniques known to those skilled in theart.

In one embodiment, the process according to the invention furthercomprises at least one step of incorporating at least one polyol.

In one embodiment, the process according to the invention ischaracterized in that the polyols are chosen from the group consistingof glycerol, sorbitol, propylene glycol, xylitol, mannitol, erythritol,maltitol and lactitol, alone or as a mixture.

In one embodiment, the process according to the invention furthercomprises at least one step of mixing a solution of at least oneadditional compound with the hydrogel obtained in the hydration step.

In one embodiment, the process according to the invention ischaracterized in that the step of mixing a solution of at least oneadditional compound with the hydrogel obtained in the hydration stepcomes before the homogenization step. In one embodiment, the processaccording to the invention is characterized in that the step of mixing asolution of at least one additional compound with the hydrogel obtainedin the hydration step is carried out at a temperature suitable for theproduction process. In one embodiment, it is carried out at ambienttemperature.

The invention also relates to the use of an injectable sterilizedaqueous composition according to the invention, for the formulation of acomposition for filling in wrinkles, or for correcting skin defects orvolume defects (cheek bones, chin, lips).

Given that the use relates to an injectable sterilized aqueouscomposition according to the invention, all of the embodimentsapplicable to the injectable sterilized aqueous composition according tothe invention are applicable to the use of the injectable sterilizedaqueous composition according to the invention, for the formulation of acomposition for filling in wrinkles, or for correcting skin defects orvolume defects (cheek bones, chin, lips).

The invention also relates to the use of an injectable sterilizedaqueous composition according to the invention, for the formulation of acomposition that can be injected into a joint to replace or supplementdeficient synovial fluid.

Given that the use relates to an injectable sterilized aqueouscomposition according to the invention, all of the embodimentsapplicable to the injectable sterilized aqueous composition according tothe invention are applicable to the use of the injectable sterilizedaqueous composition according to the invention, for the formulation of acomposition that can be injected into a joint to replace or supplementdeficient synovial fluid.

The invention also relates to an injectable sterilized aqueouscomposition according to the invention, for use in replacing orsupplementing deficient synovial fluid.

The invention also relates to a kit comprising an injectable sterilizedaqueous composition according to the invention, packaged in syringes andsterilized after packaging.

The invention also relates to a kit comprising an injectable sterilizedaqueous composition according to the invention, packaged in single-dosebottles and sterilized after packaging.

Given that the kit comprises an injectable sterilized aqueouscomposition according to the invention, all of the embodimentsapplicable to the injectable sterilized aqueous composition according tothe invention are applicable to the kit comprising an injectablesterilized aqueous composition according to the invention, packaged insyringes or in single-dose bottles and sterilized after packaging.

The invention also relates to the use of an injectable sterilizedaqueous composition according to the invention, for the formulation of acomposition for filling in wrinkles, or for correcting skin defects orvolume defects (cheek bones, chin, lips).

The invention also relates to an injectable sterilized aqueouscomposition according to the invention, for use in filling in wrinklesand/or in correcting skin defects.

The invention also relates to the use of an injectable sterilizedaqueous composition according to the invention, for the formulation of acomposition that can be injected into a joint to replace or supplementdeficient synovial fluid.

The invention also relates to an injectable sterilized aqueouscomposition according to the invention, for use in replacing orsupplementing deficient synovial fluid.

The invention also relates to the use of an injectable sterilizedaqueous composition according to the invention, for the formulation of acomposition for filling in wrinkles.

The invention also relates to the use of an injectable sterilizedaqueous composition according to the invention, for the formulation of aviscosupplementation composition.

The invention also relates to an injectable sterilized aqueouscomposition according to the invention, for use as a medicament.

The applications targeted are more particularly the applicationscommonly observed in the context of injectable viscoelastic products andpolysaccharides used or potentially useable in the followingpathological conditions or treatments:

-   -   esthetic injections in the face: for filling in wrinkles, skin        defects or volume defects (cheek bones, chin, lips);    -   volumizing injections in the body: breast and buttock        augmentation, G-spot augmentation, vaginoplastie, reconstruction        of the vaginal labia, penis enlargement;    -   treatment for arthrosis, injection into the joint to replace or        supplement deficient synovial fluid;    -   peri-urethral injection for the treatment of urinal incontinence        caused by sphincter insufficiency;    -   post-surgical injection for preventing peritoneal adhesions in        particular;    -   injection following surgery for long-sightedness by scleral        laser incisions;    -   Injection into the vitreous cavity;    -   Injection during cataract surgery;    -   injection into genital parts.

More particularly, in esthetic surgery, according to its viscoelasticproperties and persistence properties, the injectable sterilized aqueouscomposition obtained according to the process of the invention may beused:

-   -   for filling in fine, moderate or deep wrinkles, and may be        injected using narrow-diameter needles (27 gauge, for example);    -   as a volumizing product with injection using needles which are        of larger diameter, from 22 to 26 gauge, for example, and longer        (30 to 40 mm, for example); in this case, its cohesive nature        will ensure that it stays at the site of injection.

The injectable sterilized aqueous composition according to the inventionalso finds major application in joint surgery and in dental surgery, forthe filling in of periodontal pockets, for example.

These use examples are not in any way limiting, and the injectablesterilized aqueous composition according to the present invention beingmore broadly envisaged for:

-   -   filling in volumes;    -   generating spaces within certain tissues, thus promoting the        optimum functioning thereof;    -   replacing deficient physiological fluids.

EXAMPLES

a) Abbreviations Used

In the examples, the following abbreviations are used:

-   -   AL: local anesthetic;    -   Po: polyol;    -   CA: additional compound;    -   ARTI: articaine;    -   BUPI: bupivacaine;    -   MEPI: mepivacaine;    -   PROC: procaine;    -   ROPI: ropivacaine;    -   HA: hyaluronic acid;    -   % G′: % change in the elastic component G′ compared with the        reference composition.

The percentage change in the elastic component G′ is defined as being:

% change G′=100×(Y−Y′)/Y

with Y=percentage loss of the elastic component G′ on sterilization ofthe reference composition,and Y′=percentage loss of the elastic component G′ on sterilization ofthe composition tested;

-   -   % η: % change in the viscosity n compared with the reference        composition.        The percentage change in the viscosity n is defined as being:

% change η=100×(Z−Z′)/Z

with Z=percentage loss of viscosity η on sterilization of the referencecomposition,and Z′=percentage loss of viscosity n on sterilization of thecomposition tested;

-   -   MAL: maltitol;    -   MAN: mannitol.

b) Production of Gels

Crosslinked Hyaluronic Acid Gels

The gels comprising crosslinked hyaluronic acid are obtained accordingto the procedure described in patent application WO 2009/071697 in thename of the applicant, from fibers of sodium hyaluronate (NaHA) and ofbutanediol diglycidyl ether (BDDE).

Local Anesthetics

The local anesthetics are dissolved in a solution of stabilizedphosphate buffer before they are incorporated into the hyaluronic acidgels.

Polyol

The polyol is dissolved in a solution of phosphate buffer before it isincorporated into the hyaluronic acid gels.

Sterilization

The resulting compositions are packaged in syringes which are sterilizedby steam autoclaving (T=121° C., 10 min).

c) Rheological Property Measurements

The elastic components G′ of the compositions comprising crosslinkedhyaluronic acid before and after sterilization by steam autoclaving weremeasured on a TA Instrument AR 2000 Ex rheometer, in oscillating mode at25° C., the values of the elastic component G′ being recorded at afrequency of 1 Hz.

The viscosity η of the compositions is measured on a TA Instruments AR2000 Ex rheometer, with applied stress at 25° C. The viscosity value isrecorded at a stress of 0.02 s⁻¹, except when specified in the example.

Example 1

Example 1 Illustrates the effects of mannitol on the rheologicalproperties during heat sterilization of a gel of hyaluronic acid havinga weight-average molecular weight of 3×10⁶ Da at a concentration of 20mg/g with a degree of crosslinking X=0.12.

For all the measurements, a reference composition is formulated,replacing the aqueous solution of polyol with an equivalent amount ofaqueous solution of phosphate buffer.

TABLE 1 AL Po CA [AL] [Po] [CA] N ° nature (mg/g) nature (mg/g) nature(mg/g) [HA]/[AL] % G′ 1 none 0 MAN  0 none 0 n/a  0 2 none 0 MAN  5 none0 n/a 31 3 none 0 MAN 35 none 0 n/a 36

In conclusion, the addition of mannitol results in an increase in G′during sterilization by autoclaving. This is in agreement with theeffects obtained in the prior art.

Example 2

Example 2 Illustrates the effects of various local anesthetics on therheological properties during heat sterilization of hyaluronic acid gelscomprising a polyol.

Example 2-A

Example 2-a illustrates the influence of various local anesthetics onthe rheological properties during heat sterilization of a gel ofhyaluronic acid having a weight-average molecular weight of 3×10⁶ Da ata concentration of 20 mg/g with a degree of crosslinking X=0.06,comprising mannitol.

The [HA]/[AL] ratio is 6.67.

The [Po]/[AL] ratio is 11.66.

For all the measurements, a reference composition is formulated,replacing the aqueous solution of local anesthetic within an equivalentamount of aqueous solution of phosphate buffer.

TABLE 2 AL Po CA [AL] [Po] [CA] N ° nature (mg/g) nature (mg/g) nature(mg/g) [HA]/[AL] % G′ 4 none 0 MAN 35 none 0 n/a   0 5 ARTI 3 MAN 35none 0 6.67 −121 6 BUPI 3 MAN 35 none 0 6.67 −143 7 ROPI 3 MAN 35 none 06.67  −76

In conclusion, the addition of articaine, of bupivacaine or ofropivacaine results in a decrease in the G′ of the compositions alreadycomprising mannitol, during sterilization by autoclaving. This isparticularly surprising if the results obtained by Anteis with regard tolidocaine in application WO 2010/052430 are in particular taken intoaccount.

Example 2-B

Example 2-b illustrates the influence of various local anesthetics onthe rheological properties during heat sterilization of a gel ofhyaluronic acid having a weight-average molecular weight of 3×10⁶ Da ata concentration of 20 mg/g with a degree of crosslinking X=0.06,comprising maltitol.

The [HA]/[AL] ratio is 6.67.

The [Po]/[AL] ratio is 11.66.

For all the measurements, a reference composition is formulated,replacing the aqueous solution of local anesthetic with an equivalentamount of aqueous solution of phosphate buffer.

TABLE 3 AL Po CA [AL] [Po] [CA] N ° nature (mg/g) nature (mg/g) nature(mg/g) [HA]/[AL] % G′  8 none 0 MAL 35 none 0 n/a   0  9 ARTI 3 MAL 35none 0 6.67  −88 10 BUPI 3 MAL 35 none 0 6.67 −134 11 ROPI 3 MAL 35 none0 6.67  −68

In conclusion, the addition of articaine, of bupivacaine or ofropivacaine results in a decrease in the G′ of the compositions alreadycomprising maltitol, during the sterilization by autoclaving. This isparticularly surprising if the results obtained by Antels with regard tolidocaine in application WO 2010/052430 are in particular taken intoaccount.

Example 2-C

Example 2-c illustrates the influence of procaine on the rheologicalproperties during heat sterilization of a gel of hyaluronic acid havinga weight-average molecular weight of 3×10⁶ Da at a concentration of 20mg/g with a degree of crosslinking X=0.06, comprising mannitol.

The [HA]/[AL] ratio is 6.67.

The [Po]/[AL] ratio is 11.66.

For all the measurements, a reference composition is formulated,replacing the aqueous solution of local anesthetic with an equivalentamount of aqueous solution of phosphate buffer.

TABLE 4 AL Po CA [AL] [Po] [CA] N ° nature (mg/g) nature (mg/g) nature(mg/g) [HA]/[AL] % G′ 12 none 0 MAN 35 none 0 n/a  0 13 PROC 3 MAN 35none 0 6.67 −12

In conclusion, the addition of procaine results in a decrease in the G′of the compositions already comprising mannitol, during thesterilization by autoclaving. This is particularly surprising if theresults obtained by Antels with regard to lidocaine in application WO2010/052430 are in particular taken into account.

Examples 2-a, 2-b and 2-c illustrate that the addition of at least onelocal anesthetic chosen from the group consisting of benzocaine,chloroprocaine, procaine, etidocaine, aptocaine, chlorobutanol,diamocaine, dyclonine, guafecainol, polidocanol, mepivacaine,prilocaine, articaine, bupivacaine, ropivacaine, tetracaine and saltsthereof and isolated isomers thereof results in a decrease in the G′ ofcompositions already comprising at least one polyol, duringsterilization by autoclaving.

Example 2-D

Example 2-d illustrates the influence of mepivacaine on the rheologicalproperties during heat sterilization of a gel of non-crosslinkedhyaluronic acid having a weight-average molecular weight of 3×10⁶ Da ata concentration of 20 mg/g, comprising mannitol.

The [HA]/[AL] ratio ranges from 20 to 2.

For all the measurements, a reference composition is formulated,replacing the aqueous solution of local anesthetic with an equivalentamount of aqueous solution of phosphate buffer.

TABLE 5 AL Po CA [AL] [Po] [CA] N ° nature (mg/g) nature (mg/g) nature(mg/g) [HA]/[AL] % η 14 none  0 MAN 35 none 0 n/a  0 15 MEPI  1 MAN 35none 0 20 −43 16 MEPI  3 MAN 35 none 0 6.67 −62 17 MEPI  6 MAN 35 none 03.33 −67 18 MEPI 10 MAN 35 none 0 2 −68

In conclusion, the addition of mepivacaine results in a decrease in then of the compositions based on non-crosslinked hyaluronic acid alreadycomprising mannitol, during sterilization by autoclaving.

Example 3

Example 3 Illustrates the influence of mepivacaine on the rheologicalproperties during heat sterilization of a gel of hyaluronic acid havinga weight-average molecular weight of 3×10⁶ Da at a concentration of 20mg/g with a degree of crosslinking X=0.06, comprising mannitol.

The [HA]/[AL] ratio is 6.67.

The [Po]/[AL] ratio is 11.66.

For all the measurements, a reference composition is formulated,replacing the aqueous solution of local anesthetic with an equivalentamount of aqueous solution of phosphate buffer.

TABLE 6 AL Po CA F(N) 13 [AL] [Po] [CA] [HA]/ mm/min η 0.017^(s−1) η1000^(s−1) N ° nature (mg/g) nature (mg/g) nature (mg/g) [AL] % G′ 27G1/2 (Pa · s) (Pa · s) 19 none 0 MAN 35 none 0 n/a   0 21 3057 1.4 20MEPI 3 MAN 35 none 0 6.67 −109 20 2538 1.3

In conclusion, the addition of mepivacaine results in a decrease in theG′ of the compositions already comprising mannitol, during sterilizationby autoclaving. This is particularly surprising if the results obtainedby Anteis with regard to lidocaine in application WO 2010/052430 are inparticular taken into account.

Furthermore, the addition of mepivacaine results in a decrease in theviscosity at low shear rate (0.017 s⁻¹), but not at high shear rate(1000 s⁻¹). Thus, the injectability (linked to the viscosity at highshear rate) is not significantly modified.

What is claimed is:
 1. An injectable sterilized aqueous composition comprising at least one hyaluronic acid, at least one polyol and at least one local anesthetic chosen from the group consisting of benzocaine, chloroprocaine, procaine, etidocaine, aptocaine, chlorobutanol, diamocaine, dyclonine, guafecainol, polidocanol, mepivacaine, prilocaine, articaine, bupivacaine, ropivacaine, tetracaine and salts thereof and isolated isomers thereof.
 2. The injectable sterilized aqueous composition as claimed in claim 1, which comprises at least one non-crosslinked hyaluronic acid or a salt thereof, alone or as a mixture.
 3. The injectable sterilized aqueous composition as claimed in claim 1, which comprises at least one crosslinked hyaluronic acid or a salt thereof, alone or as a mixture.
 4. The injectable sterilized aqueous composition as claimed in claim 1, wherein the at least one polyol is chosen from the group consisting of glycerol, sorbitol, propylene glycol, xylitol, mannitol, erythritol, maltitol and lactitol, alone or as a mixture.
 5. The injectable sterilized aqueous composition as claimed in claim 1, wherein the concentration of the at least one hyaluronic acid [HA] is between 2 mg/g and 50 mg/g of total weight of said composition.
 6. The injectable sterilized aqueous composition as claimed in claim 1, wherein the concentration of the at least one hyaluronic acid [HA] is 20 mg/g of total weight of said composition.
 7. The injectable sterilized aqueous composition as claimed in claim 1, wherein the concentration of the at least one polyol [Po] is between 0.01 mg/g and 50 mg/g.
 8. The injectable sterilized aqueous composition as claimed in claim 1, wherein the concentration of the at least one local anesthetic [AL] is between 0.01 mg/g and 50 mg/g.
 9. The injectable sterilized aqueous composition as claimed in claim 1, wherein the weight ratio between the concentration of the at least one polyol [Po] and the concentration of the at least one local anesthetic [AL]:[Po]/[AL] is between 0.0002 and 5000; 0.0002≤[Po]/[AL]≤5000.
 10. The injectable sterilized aqueous composition as claimed in claim 1, wherein the weight ratio between the concentration of the at least one hyaluronic acid [HA] and the concentration of the at least one local anesthetic [AL]:[HA]/[AL] is between 0.1 and 50; 0.1≤[HA]/[AL]≤50.
 11. The injectable sterilized aqueous composition as claimed in claim 1, wherein the sterilization is carried out by heat, moist heat, gamma (γ) radiation, or by accelerated electron beam.
 12. The injectable sterilized aqueous composition as claimed in claim 1, which further comprises at least one additional compound.
 13. A process for adapting the rheological properties of a sterilized injectable aqueous composition comprising at least one polyol, which comprises the addition to said composition, before the sterilization step, of at least one local anesthetic chosen from the group consisting of benzocaine, chloroprocaine, procaine, etidocaine, aptocaine, chlorobutanol, diamocaine, dyclonine, guafecainol, polidocanol, mepivacaine, prilocaine, articaine, bupivacaine, ropivacaine, tetracaine and salts thereof and isolated isomers thereof.
 14. A process for producing an injectable sterilized aqueous composition as claimed in claim 1, which comprises at least the following steps: 1) a step of hydration in a buffer solution at a pH close to physiological pH of the fibers of at least one hyaluronic acid or a salt thereof, alone or as a mixture, so as to obtain a hydrogel; 2) a step of incorporation of at least one polyol in aqueous solution into the hydrogel obtained in the previous step; 3) a step of incorporation of at least one local anesthetic chosen from the group consisting of benzocaine, chloroprocaine, procaine, etidocaine, aptocaine, chlorobutanol, diamocaine, dyclonine, guafecainol, polidocanol, mepivacaine, prilocaine, articaine, bupivacaine, ropivacaine and tetracaine and salts thereof and isolated isomers thereof, into the hydrogel obtained in the previous step; 4) a homogenization step; and 5) a sterilization step; it being possible for said steps 2) and 3) to be carried out in any order or simultaneously.
 15. The production process as claimed in claim 14, which further comprises at least one crosslinking step simultaneously with or subsequent to step
 1. 16. The injectable sterilized aqueous composition as claimed in claim 1, for the formulation of a composition for filling in wrinkles, or for correcting skin defects or volume defects (cheek bones, chin, lips).
 17. The injectable sterilized aqueous composition as claimed in claim 1, for the formulation of a composition that can be injected into a joint to replace or supplement deficient synovial fluid.
 18. The injectable sterilized aqueous composition as claimed in claim 1, for use in replacing or supplementing deficient synovial fluid.
 19. A kit comprising an injectable sterilized aqueous composition as claimed in claim 1, packaged in syringes and sterilized after packaging. 